Individuals vary significantly in their propensity to experiment with drugs of abuse and to become addicted to them. Some may seek drugs as an aspect of sensation seeking or risk taking behavior. Others may do so as a result of social or psychological stress. The purpose of this proposal is to investigate the neurobiological basis for these individual differences in vulnerability to abusing drugs. The basic premise is that the combination of genetic, developmental and environmental factors that lead to differences in vulnerability is expressed in the brain, and needs to be understood at that level. The primary site of expression of relevant genes is likely in the context of the emotional brain circuits that regulate responsiveness to stress and to the environment, and that become dysregulated in addiction and in mood disorders. In order to investigate the neuronal basis of individual differences in drug abuse, this proposal relies on a behavioral model that distinguishes rats that are sensation or novelty-seeking from those that are not. These sensation-seeking animals learn to administer drugs, such as amphetamine, much more rapidly although the drugs are equally rewarding to them. We plan to characterize the patterns of gene expression in rats that exhibit different phenotypes of sensation-seeking behavior. We plan to focus on stress related genes and determine the possible presence of unique neuronal phenotypes associated with sensation-seeking and drug-taking behavior. We then plan to use a model of psychosocial stress, social defeat, to study the impact of such stress on the rate of acquisition of drug taking behavior and the associated patterns of gene expression in the emotional circuits of these differing animals. These studies should begin to give us a glimpse of how gene expression and brain circuits may differ in individuals with differing tendencies to abuse drugs, and how social stress can impact on these systems, further modifying them and leading to distinctive behavioral responses.